Use of Umbilical Core Blood derived HSC to Treat Acute Kidney Injury

描述(申请人提供)：该项目的总体目标是采用一种创新的方法来开发从人脐血源造血干细胞(UCB-HSC)中提取的细胞治疗药物来治疗急性肾损伤(AKI)。急性肾损伤不仅发病率和死亡率高，而且常导致慢性肾脏疾病。目前，AKI还没有特效的治疗方法。一旦肾功能衰竭，慢性肾脏疾病的治疗费用为医疗保险支出的20%。新的更有效的治疗方法，如基于干细胞的治疗，将产生重大的临床和财务影响。我们发现，小鼠骨髓HSC在体外经细胞因子和致肾因子处理1周后，可以被重新编程为表达肾脏发育基因的细胞。用组蛋白脱乙酰酶(HDAC)抑制剂曲古抑素A(TSA)进一步处理细胞，可将重编程从6%提高到38%。将重新编程的细胞注射到肾缺血损伤的小鼠体内，加速了肾脏结构和功能的恢复。为了开始将这些发现转化为临床，我们建议对人的UCB-HSC重新编程，并在AKI的小鼠模型中测试它们的治疗效果。脐带血中含有较高浓度的CD34+干细胞和祖细胞。这些细胞可以很容易地分离出来，不会对捐赠者造成风险。UTSW附属的Parkland纪念医院每天接生约47名婴儿，这确保了充足的细胞分离供应。采用类似于小鼠骨髓HSC的方法，来自人脐血的CD34+细胞将在体外用细胞因子、致肾因子和HDAC抑制剂TSA处理，以诱导造血细胞向肾脏的转换。诱导细胞的特征是一组肾脏发育基因的表达，以及它们分化为上皮细胞和形成管状结构的能力(目标1)。此外，诱导的细胞将被移植到急性缺血再灌注损伤的小鼠体内，以测试它们是否促进了肾脏功能和结构的恢复。通过直接将细胞替换到修复的小管和/或旁分泌效应来减少上皮和内皮损伤并增加固有的肾细胞再生来保护肾脏的机制将被研究(目标2)。该项目可能代表着干细胞生物学向床边转化的第一步。我们有信心凭借我们的经验和努力，我们将能够在头9个月内完成目标1的研究，并在未来15个月内完成目标2的研究。 公共卫生相关性：急性肾损伤具有高发病率和高死亡率。目前还没有特效的治疗方法。干细胞为肾脏疾病提供了治疗潜力。这项应用的目标是开发来自人脐血源干细胞的细胞治疗剂来治疗急性肾损伤。

DESCRIPTION (provided by applicant): The overall goal of this project is to take an innovative approach to develop cell therapeutic agents from human umbilical cord blood-derived hematopoietic stem cells (UCB-HSC) to treat acute kidney injury (AKI). Acute kidney injury not only has a high morbidity and mortality rate but often leads to chronic kidney disease. At the present time, there is no specific treatment for AKI. Once the kidney fails, treatment of chronic kidney disease costs 20% Medicare expenditure. New and more effective treatments, such as stem cell-based therapy, will have significant clinical and financial impact. We have shown that mouse bone marrow HSC can be reprogrammed into cells expressing renal developmental genes after 1 week of treatment with cytokines and nephrogenic factors in vitro. Further treatment of the cells with a histone deacetylase (HDAC) inhibitor trichostatin A (TSA) enhances reprogramming from 6% to 38%. Injection of the reprogrammed cells into mice with renal ischemic injury accelerates kidney structural and functional recovery. To begin to translate these findings clinically, we propose to reprogram human UCB- HSC and test their therapeutic effect in mouse models of AKI. Umbilical cord blood contains higher concentrations of CD34+ stem and progenitor cells. The cells can be isolated easily without risk to the donors. The UTSW-affiliated Parkland Memorial Hospital delivers about 47 infants a day, which ensures an abundant supply for cell isolation. Using a similar approach for the mouse bone marrow HSC, CD34+ cells from human umbilical cord blood will be treated in vitro with cytokines, nephrogenic factors and a HDAC inhibitor TSA to induce hematopoietic-to-renal conversion. The induced cells will be characterized for the expression of a panel of renal developmental genes, and their ability to differentiate into epithelial cells and form tubular structures (Aim 1). Furthermore, the induced cells will be transplanted into mice with acute ischemia-reperfusion injury to test whether they accelerate renal functional and structural recovery. The mechanisms of renal protection by direct cell replacement into the repairing tubules and/or paracrine effect to decrease epithelial and endothelial injury and increase intrinsic renal cell regeneration will be investigated (Aim 2). This project may represent the first step toward translation of stem cell biology to the bedside. We are confident that with our experience and dedication, we will be able to complete the studies in Aim 1 in the first 9 months and the studies in Aim 2 in the next 15 months. PUBLIC HEALTH RELEVANCE: Acute kidney injury has high morbidity and high mortality. There is no specific and effective treatment at the present time. Stem cells offer therapeutic potential for kidney disease. The goal of this application is to develop cell therapeutic agents from human umbilical cord blood-derived stem cells to treat acute kidney injury.